U.S. patent application number 11/475486 was filed with the patent office on 2007-01-11 for compositions and methods for treatment of cycle-related symptoms.
This patent application is currently assigned to Wyeth. Invention is credited to Ginger Dale Constantine, Gary Sondermann Grubb.
Application Number | 20070009594 11/475486 |
Document ID | / |
Family ID | 37440889 |
Filed Date | 2007-01-11 |
United States Patent
Application |
20070009594 |
Kind Code |
A1 |
Grubb; Gary Sondermann ; et
al. |
January 11, 2007 |
Compositions and methods for treatment of cycle-related
symptoms
Abstract
Methods are provided for treating cycle-related symptoms through
administration of at least one progestin and at least one estrogen
to a female subject.
Inventors: |
Grubb; Gary Sondermann;
(Newtown Square, PA) ; Constantine; Ginger Dale;
(Malvern, PA) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
37440889 |
Appl. No.: |
11/475486 |
Filed: |
June 26, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60695077 |
Jun 28, 2005 |
|
|
|
Current U.S.
Class: |
424/464 ;
514/170 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61P 15/00 20180101;
A61K 31/57 20130101; A61P 5/30 20180101; A61K 31/56 20130101; A61K
31/565 20130101; A61K 31/565 20130101; A61P 15/18 20180101; A61K
31/57 20130101; A61K 31/56 20130101; A61P 5/24 20180101 |
Class at
Publication: |
424/464 ;
514/170 |
International
Class: |
A61K 31/56 20060101
A61K031/56; A61K 9/20 20060101 A61K009/20 |
Claims
1. A method for treating a female subject having cycle-related
symptoms comprising administering an effective amount of at least
one progestin and at least one estrogen to said female subject,
wherein said effective amount is administered daily for at least
about 100 days.
2. The method of claim 1 wherein said female subject has one or
more psychological or physical cycle-related symptoms and said
effective amount is effective for treating said one or more
psychological or physical symptoms.
3. The method of claim 2 wherein said female subject has
dysmenorrhea and said effective amount is effective for treating
dysmenorrhea.
4. The method of claim 2 wherein said female subject has moderate
to severe cycle-related symptoms and said effective amount is
effective for treating moderate to severe cycle-related
symptoms.
5. The method of claim 2 wherein said female subject has mild to
moderate cycle-related symptoms and said effective amount is
effective for treating mild to moderate cycle-related symptoms.
6. The method of claim 1 wherein at least about 4 .mu.g of
levonorgestrel, or a progestin dosage of corresponding potency, is
administered.
7. The method of claim 1 wherein from about 60 .mu.g to about 110
.mu.g of levonorgestrel, or a progestin dosage of corresponding
potency, is administered.
8. The method of claim 1 wherein at least about 1 .mu.g of ethinyl
estradiol, or an estrogen dosage of corresponding potency, is
administered.
9. The method of claim 1 wherein from about 15 .mu.g to about 25
.mu.g of ethinyl estradiol, or an estrogen dosage of corresponding
potency, is administered.
10. The method of claim 1 wherein said at least one progestin is
chlormadinone acetate, norethisterone acetate, cyproterone acetate,
desogestrel, gestodene, drospirenone, etonorgestrel, norgestimate,
norelgestromin, or levonorgestrel.
11. The method of claim 1 wherein said at least one estrogen is
ethinyl estradiol, mestranol, estradiol, estriol, estrone, or
estrane.
12. The method of claim 10 wherein said at least one progestin is
levonorgestrel administered at a dosage not greater than 90 .mu.g
per day, or a progestin dosage of corresponding potency is
administered.
13. The method of claim 11 wherein said at least one estrogen is
ethinyl estradiol administered at a dosage not greater than 20
.mu.g per day, or an estrogen dosage of corresponding potency is
administered.
14. The method of claim 1 wherein said at least one estrogen is
ethinyl estradiol administered at a dosage of approximately 20
.mu.g per day, and said at least one progestin is levonorgestrel
administered at a dosage of approximately 90 .mu.g per day, or an
estrogen dosage of corresponding potency and a progestin dosage of
corresponding potency is administered.
15. The method of claim 1 wherein said effective amount is
administered orally, transdermally, or via depot to the
subject.
16. The method of claim 1 wherein said effective amount is
administered daily for at least about 4 months.
17. The method of claim 1 wherein said effective amount is
administered daily for at least about 6 months.
18. The method of claim 1 wherein said effective amount is
administered daily for at least about 9 months.
19. The method of claim 1 wherein said effective amount is
administered daily for at least about 12 months.
20. The method of claim 1 wherein said effective amount is
administered in a dosage form.
21. The method of claim 1 wherein said dosage form is a tablet or
capsule.
22. The method of claim 20 wherein said dosage form is administered
orally, transdermally or via depot to the subject.
23. The method of claim 1 further comprising determining an extent
to which said female subject has cycle-related symptoms.
24. The method of claim 23, further comprising determining an
extent to which said female subject has dysmenorrhea.
25. The method of claim 23, further comprising determining an
extent to which said female subject has moderate to severe
cycle-related symptoms.
26. The method of claim 23 further comprising determining an extent
to which said female subject has mild to moderate cycle-related
symptoms.
27. The method of claim 23 wherein said determination is made
before said administering step.
28. The method of claim 23 wherein said determination is made after
said administering step.
29. A kit for treating a female subject having cycle-related
symptoms comprising at least about 100 dosage forms that
individually comprise at least one progestin and at least one
estrogen.
30. The kit of claim 29 wherein each of said dosage forms comprise
at least about 4 .mu.g of levonorgestrel or a progestin dosage form
of corresponding potency.
31. The kit of claim 29 wherein each of said dosage forms comprise
from about 60 .mu.g to about 110 .mu.g of levonorgestrel or a
progestin dosage form of corresponding potency.
32. The kit of claim 29 wherein each of said dosage forms comprise
at least about 1 .mu.g of ethinyl estradiol or an estrogen dosage
form of corresponding potency.
33. The kit of claim 29 wherein each of said dosage forms comprise
from about 15 .mu.g to about 25 .mu.g of ethinyl estradiol or an
estrogen dosage form of corresponding potency.
34. The kit of claim 29 wherein said at least one progestin is
progesterone, chlormadinone acetate, norethisterone acetate,
cyprotherone acetate, desogestrel, drospirenone, etonorgestrel,
norgestimate, norelgestromin, or levonorgestrel.
35. The kit of claim 29 wherein said at least one estrogen is
ethinyl estradiol, mestranol, estradiol, estriol, estrone, or
estrane.
36. The kit of claim 34 wherein each of said dosage forms comprise
levonorgestrel in an amount no greater than 90 .mu.g or a progestin
dosage form of corresponding potency.
37. The kit of claim 35 wherein each of said dosage forms comprise
ethinyl estradiol in an amount no greater than 20 .mu.g or an
estrogen dosage form of corresponding potency.
38. The kit of claim 29 wherein each of said dosage forms comprise
approximately 20 .mu.g ethinyl estradiol and approximately 90 .mu.g
levonorgestrel, or an estrogen dosage form and a progestin dosage
form of corresponding potency.
39. The kit of claim 29 that comprises at least about 185 of said
dosage forms.
40. The kit of claim 29 that comprises at least about 275 of said
dosage forms.
41. The kit of claim 29 that comprises is at least about 365 of
said dosage forms.
42. The kit of claim 29 wherein said dosage forms are tablets,
capsules, or a combination thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/695,077, filed Jun. 28, 2005, which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] In one aspect, the present invention relates to methods for
treating cycle-related symptoms through administration of at least
one progestin and at least one estrogen to a female subject.
BACKGROUND OF THE INVENTION
[0003] The term "cycle-related symptoms" refers to physical and
psychological symptoms associated with a woman's menstrual cycle
arising in the luteal phase of the menstrual cycle. It has been
reported that most women report experiencing cycle-related
symptoms. The symptoms generally disappear soon after the onset of
menstruation, and the patient has markedly reduced or no symptoms
during the rest of the follicular phase. The cyclical occurrence of
the symptoms is the key characteristic of cycle-related
symptoms.
[0004] Cycle-related symptoms occur in about 95% of women with
their menstrual cycles. About one-third of those women experience
moderate to severe cycle-related symptoms. Women vary in the
number, type, severity, and pattern of these cycle-related symptoms
that occur before menstruation. One thing common to all the types
of cyclic-related symptoms is the decrease or elimination of the
symptoms in the two weeks after menstruation up to the time of
ovulation.
[0005] The use of extended oral contraceptive for extended cycles
(i.e., greater than consecutive 21 days of active drug) to reduce
cycle-related symptoms with tolerable irregular bleeding has shown
variable success. Extension of active pill use to produce cycles
varying from 42 to 84 days has been studied in small populations,
with different oral contraceptive formulations, and with variable
success regarding cycle control. Tonkelaar and Oddens,
Contraception, 59: 357-362, 1999; U.S. patent application Ser. No.
2003/0139381. Extending cyclical oral contraceptive use from 21 to
42 days reduced bleeding and need for hygiene products. Miller and
Hughes, Obstet. Gynecol., 101: 653-661, 2003. A need exists in the
art for an improved method for administering an oral contraceptive
to women to relieve cycle-related symptoms.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides methods for
treating a female subject having cycle-related symptoms. Certain
methods according to the invention comprise administering an
effective amount of at least one progestin and at least one
estrogen to said female subject, wherein said effective amount is
administered daily for at least about 100 days. The female subject
can have cycle-related symptoms and said effective amount can be
effective for treating cycle-related symptoms. The female subject
can have cycle-related symptoms, for example, dysmenorrhea or
moderate to severe cycle-related symptoms, and said effective
amount can be effective for treating cycle-related symptoms of
dysmenorrhea or other physical and psychological cycle-related
symptoms. Preferred among such methods are those that comprise
administering an effective amount of at least one progestin and at
least one estrogen to the female subject. Effect dose refers to the
combined amount of steroid in a daily dosage unit taking into
account the potency of a given steroid. The effect dose of a given
steroid can be determined by one skilled in the art. In certain
embodiments, at least about 4 .mu.g of the at least one progestin
(preferably from about 60 to about 120 .mu.g of levonorgestrel
(LNG), or more preferably about 90 .mu.g) and/or at least about 1
.mu.g of the at least one estrogen (or preferably from about 15 to
about 25 .mu.g of ethinyl estradiol (EE), or more preferably about
20 .mu.g) is administered.
[0007] Also provided are methods for treating a female subject
having cycle-related symptoms that comprise administering at least
one progestin and at least one estrogen to a female subject daily
for at least about 100 days. Preferred among such methods are those
that involve daily administration for at least about 4 months, for
at least about 6 months, more preferably at least about 9 months,
or even more preferably for at least about 12 months. In certain
methods, the female subject has cycle-related symptoms and the at
least one progestin and at least one estrogen are administered in
an amount effective for the treatment thereof. In still further
methods, at least one progestin and at least one estrogen are
administered in an amount effective for contraception.
[0008] The invention also provides kits for treating a female
subject having cycle-related symptoms, comprising at least about
100 dosage forms that individually comprise at least one progestin
and at least one estrogen. In preferred kits, the dosage forms
comprises about 90 .mu.g of levonorgestrel (LNG) or the at least
one progestin of equivalent potencies and/or about 20 .mu.g of
ethinyl estradiol (EE) or the at least one estrogen of equivalent
potencies. The kits can take the form of, for example, blister
packs or other suitable dosage form arrays, and can include at
least about 100 such dosage forms, at least about 185 such dosage
forms, preferably at least about 275 such dosage forms, or more
preferably at least about 365 such dosage forms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows the 17-item Penn Daily Symptom Report (DSR) and
premenstrual total score for the moderate to severe cycle-related
symptoms subgroup of the cycle-related symptoms study (CRSS).
[0010] FIG. 2 shows 17-item Penn Daily Symptom Report (DSR)
postmenstrual subscale score for the moderate to severe
cycle-related symptoms subgroup of the cycle-related symptoms study
(CRSS).
[0011] FIG. 3 shows Endicott Work Productivity Scale (EWPS) total
score for the moderate to severe cycle-related symptoms subgroup of
the cycle-related symptoms substudy.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0012] Certain methods of the invention involve treating female
subjects for cycle-related symptoms associated with the menstrual
cycle. As used herein, the term "treating" or "treatment" refers to
any indicia of success in amelioration of an injury, pathology, or
condition, including any objective or subjective parameter such as
abatement; inhibition; remission; diminishing of symptoms or making
the injury, pathology, or condition more tolerable to the patient;
slowing in the rate of degeneration or decline; making the final
point of degeneration less debilitating; or improving a subject's
physical or mental well-being. The treatment or amelioration of
symptoms can be based on objective parameters or subjective
parameters, e.g., symptom scores and quality of life evaluations;
including the results of a physical examination, neurological
examination, and/or psychiatric evaluation. Treating or treatment
of any condition disclosed herein includes preventing the onset of
symptoms in a subject that may be predisposed to the condition but
does not yet experience or exhibit symptoms of the condition
(prophylactic treatment), or inhibiting the symptoms of the
condition (slowing or arresting its development). Accordingly, the
term "treating" includes the administration of compounds or agents
to a subject to prevent or delay, to alleviate, or to arrest or
inhibit development of the symptoms or conditions associated with
the condition. A skilled medical practitioner will know how to use
standard methods to determine whether and to what extent a patient
has cycle-related symptoms. Such a determination can be made before
administration of an effective amount of progestin and estrogen
and/or after administration.
[0013] The term "cycle-related symptoms" refers to psychological
symptoms (for example, mood change, irritability, anxiety, lack of
concentration, or decrease in sexual desire) and physical symptoms
(for example, dysmenorrhea, breast tenderness, bloating, fatigue,
or food cravings) associated with a woman's menstrual cycle.
Cycle-related symptoms occur after ovulation but before menses and
usually terminate at the start of the menstrual period or shortly
thereafter. Cycle-related symptoms include, but are not limited to,
dysmenorrhea and other physical and psychological cycle-related
symptoms.
[0014] The term "dysmenorrhea" refers to painful uterine cramping
with menses. Women with dysmenorrhea may experience nausea,
vomiting, diarrhea, headaches, weakness, and/or fainting. Symptoms
may vary in severity from cycle to cycle, but generally continue
throughout the reproductive years. Dysmenorrhea can be an
incapacitating problem, causing significant disruption in a woman's
life each month.
[0015] An effective treatment for cycle-related symptoms can be
determined by administering varying amounts of progestin and
estrogen, conducting a cycle-related symptom study (CRSS), and
measuring a reduction in cycle-related symptoms. A clinical study
can evaluate cycle-related symptoms among subgroups of subjects who
report symptoms of: 1) dysmenorrhea; or 2) other physical and
psychological cycle-related symptoms. Various measurement scales
can be used to quantify cycle-related symptoms in women. For
example, a measurement of cycle-related symptoms in women can be
determined by factors of the Penn Daily Symptom Report (DSR) which
includes 17 items. See, for example, Freeman et al., Psychiatry
Research 65: 97-106, 1996, incorporated herein by reference in its
entirety. These factors can be further analyzed and subdivided into
four factor subscales: 1) mood (i.e., anxiety, irritability,
depression, nervous tension, mood swing, and feeling out of
control); 2) behavioral symptoms (i.e., poor coordination,
insomnia, confusion, headache, crying, and fatigue); 3) pain (i.e.,
aches, cramps, and breast tenderness); and 4) physical (i.e., food
cravings, swelling). As a further example, a measurement of the
effect of cycle-related symptoms on work productivity can be
determined by the Endicott Work Productivity Scale. See, for
example, Endicott and Nes, Psychopharmacology Bulletin 33: 13-16,
1997, incorporated herein by reference in its entirety.
[0016] Preferred methods for treating or diminishing cycle-related
symptoms involve administering an effective amount of at least one
progestin and at least one estrogen to a female subject. The term
"progestin," as used herein, refers to any progestationally active
compound, i.e., any compound that binds to and activates any
progesterone receptor. Representative progestins include
progesterone synthetic derivatives such as, for example, 17-hydroxy
progesterone esters, 19-nor-17-hydroxy progesterone esters,
17.alpha.-ethinyltestosterone and derivatives thereof,
17.alpha.-ethinyl-19-nor-testosterone and derivatives thereof,
norethindrone, norethindrone acetate, ethynodiol diacetate,
dydrogesterone, medroxy-progesterone acetate, norethynodrel,
allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,
norgestrienone, dimethiderome, ethisterone, cyproterone acetate,
levonorgestrel, dl-norgestrel,
d-17.alpha.-acetoxy-13.beta.-ethyl-17.alpha.-a-ethinyl-gon-4-en-3-one
oxime, gestodene, desogestrel, etonorgestrel, norgestimate and
norelgestromin. Other compounds with progestational activity used
in oral contraceptives include chlormadione, dienogest, and
drospirenone. One preferred progestin is levonorgestrel.
[0017] The term "estrogen," as used herein, refers to a group of
synthetic or natural estrogens, including steroidal and
nonsteroidal estrogens. The natural estrogens can be
mammalian-derived or plant-derived. In humans, estrogens are formed
in the ovary, possibly the adrenal cortex, the testis, and the
fetoplacental unit and have various functions in both sexes.
Estrogen is included within a class of ovulation inhibitors to
prevent breakthrough (mid-cycle) bleeding during the ovulation
cycle. The ring system of an estrogen is estrane, an 18-carbon
tetracyclic hydrocarbon nucleus that is the parent structure of the
estrogenic steroids. Estrogens typically have an aromatic A ring
with a phenolic 3-OH group and an oxygen function on C17. Estrogens
are defined as any compound that binds to and activates any
estrogen receptor. The synthetic estrogens can be for example,
ethinyl estradiol, ethynodiol diacetate, mestranol and
quinestranol. Particularly of interest are 17.alpha.-ethinyl
estradiol and esters and ethers thereof. One preferred estrogen is
17.alpha.-ethinyl estradiol. The natural estrogens can include, for
example, conjugated equine estrogens, esterified estrogens,
17.beta.-estradiol, estradiol valerate, estrone, piperazine estrone
sulphate, estriol, estriol succinate and polyestrol phosphate.
Other useable estrogens include the esters of estradiol, estrone
and ethinyl estradiol such as the acetate, sulfate, valerate or
benzoate, conjugated equine estrogens, agonist estrogens, and
selective estrogen receptor modulators.
[0018] Preferred methods for treating or diminishing cycle-related
symptoms involve administering an effective amount of at least one
progestin and at least one estrogen administered in a continuous
and uninterrupted regimen, i.e., continuous use, to a female
subject and effectively reducing cycle-related symptoms typically
associated with menses. For example, in a group of women with
dysmenorrhea, the continuous-use regimen of at least one progestin
and at least one estrogen was highly effective in significantly
reducing dysmenorrhea over the 3-month treatment period. For
example, in a group of women with moderate to severe cycle-related
symptoms, the continuous-use regimen of at least one progestin and
at least one estrogen was effective in achieving a significant
reduction in all 17 moderate to severe cycle-related symptoms
assessed over the 3-month treatment period.
[0019] The progestins and estrogens of the invention can be
administered in any amount effective to treat cycle-related
symptoms, and/or to achieve contraception. In preferred
embodiments, at least about 4 .mu.g of at least one progestin, for
example, levonorgestrel (preferably from about 4 to about 120
.mu.g, more preferably from about 60 to about 110 .mu.g, or more
preferably about 90 .mu.g) and at least about 1 .mu.g of at least
one estrogen, for example, ethinyl estradiol (preferably from about
1 to about 25 .mu.g, more preferably from about 15 to about 25
.mu.g, or more preferably about 20 .mu.g) is administered. It is
preferred that the progestin dosage be not greater than 120 .mu.g
per day (when levonorgestrel is used), and that the estrogen dosage
be not greater than 20 .mu.g per day (when ethinyl estradiol is
used). It is also preferred that the progestin and estrogen be
administered at a constant, or at least relatively constant, daily
dosage.
[0020] Although administration of ethinyl estradiol at a dosage of
approximately 20 .mu.g per day and levonorgestrel at a dosage of
approximately 90 .mu.g per day is preferred, one can use at least
about 1 .mu.g of ethinyl estradiol, (preferably from about 1 to
about 25 .mu.g, more preferably from about 15 to about 25 .mu.g, or
more preferably about 20 .mu.g), and at least about 4 .mu.g of
levonorgestrel (preferably from about 4 to about 120 .mu.g, more
preferably from about 60 to about 110 .mu.g, or more preferably
about 90 .mu.g). Other estrogens and progestins vary in potency
from ethinyl estradiol and levonorgestrel, respectively. To the
extent that other estrogens are used, either alone or in
combination with ethinyl estradiol, it is preferred that the amount
of estrogen used correspond to an equivalent pharmacologic potency
to that of the stated amounts of ethinyl estradiol. Similarly, to
the extent that other progestins are used, either alone or in
combination with levonorgestrel, it is preferred that the amount of
progestin used correspond to an equivalent pharmacologic potency to
that of the stated amounts of levonorgestrel. The correlations in
potency between the various estrogens and progestins are generally
known to those skilled in the art, see, e.g., European Patent
Application No.0 253 607; U.S. application Ser. No. 2003/0139381,
each incorporated herein by reference in their entirety and for all
purposes.
[0021] The methods for treating or diminishing cycle-related
symptoms preferably involve administering progestin and estrogen
daily for at least about 100 days. In certain embodiments,
administration is daily for at least about 4 months, daily for at
least about 6 months, daily for at least about 9 months, and/or
daily for at least about 12 months. Certain methods of the
invention involves administering estrogen and progestin, preferably
in uniform dosages, for 28 consecutive days. The 28-day treatment
cycles are continued for multiple cycles to provide a constant
dosage of estrogen and progestin for up to 6 months, up to 12
months, up to 18 months, up to 24 months or longer. In preferred
embodiments, women are administered an oral contraceptive on days 1
through 28 of the menstrual cycle containing 90 .mu.g
levonorgestrel and 20 .mu.g ethinyl estradiol per day. Thus, with a
28-day treatment cycle, there are about 13 treatment cycles per
year, thus eliminating all menstrual cycles in the year. The
treatment regimen can be continued for an extended administration
period, for example, one year or longer, or two years or longer.
There is no limit to the amount of time, as long as the woman may
potentially have menstrual cycles.
[0022] The formulations of the invention can be administered
orally, parenterally, sublingually, subdermally, transdermally,
topically, intravaginally, intranasally or buccally in a variety of
suitable dosage forms. The method of administration depends on the
types of estrogens and progestins used, as well as the amounts per
unit dosage. Pharmaceutical formulations or preparations containing
the formulations of the invention and a suitable carrier can be
solid dosage forms which includes tablets, dragees, capsules,
cachets, pellets, pills, powders or granules; topical dosage forms
which include solutions, powders, fluid emulsions, fluid
suspensions, semi-solids, ointments, pastes, creams, gels or
jellies, foams and controlled release depot entities; transdermals,
vaginal rings, buccal formulations; and parenteral dosage forms
which includes solutions, suspensions, emulsions or dry powder
comprising an effective amount of estrogen and progestin as taught
in this invention. "Depot" or "drug depot" refers to a reservoir
containing a composition that is implanted into, or in some fashion
connected to a patient such that the compound is delivered to the
patient. The depot may or may not regulate the administration of
the compound.
[0023] Pharmaceutically acceptable carriers are determined in part
by the particular composition being administered, as well as by the
particular method used to administer the composition. Accordingly,
there is a wide variety of suitable formulations of pharmaceutical
compositions for administering the hormonal contraceptive product.
It is known in the art that active ingredients can be contained in
such formulations in addition to pharmaceutically acceptable
diluents, fillers, disintegrants, binders, lubricants, surfactants,
hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers,
humectants, moisturizers, solubilizers, preservatives and the like.
The means and methods for administration are known in the art and
an artisan can refer to various pharmacologic references for
guidance. See, e.g., Remington's Pharmaceutical Sciences, Mack
Publishing Co., Easton, Pa. 18.sup.th ed., 1990; Modern
Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc., 1979; or
Goodman & Gilman's The Pharmaceutical Basis of Therapeutics,
6th Edition, MacMillan Publishing Co., New York, 1980, each
incorporated herein by reference in their entirety and for all
purposes. The pharmaceutical compositions are generally formulated
as sterile, substantially isotonic and in full compliance with all
Good Manufacturing Practice (GMP) regulations of the U.S. Food and
Drug Administration.
[0024] Generally speaking, the formulations are prepared according
to conventionally known procedures in accordance with the method of
administration. Thus, the active ingredients are prepared according
to known methods in a pharmaceutically acceptable form for
administration. These ingredients, in their required quantities are
combined with the appropriate pharmaceutical carriers such as
additives, vehicles and/or flavor ameliorating substances. These
substances can be referred to as diluents, binders and lubricants.
Gums, starches and sugars are also common terms. Typical of these
types of substances or excipients are pharmaceutical grades of
mannitol, lactose starch, magnesium stearate, sodium saccharin,
talcum, cellulose, glucose, sucrose, magnesium carbonate and the
like. The active ingredient(s) can comprise from about 0.01% by
weight to about 99.99% by weight of the total formulation and the
remainder comprises the pharmaceutically acceptable carrier. The
percentage of active ingredient(s) can vary according to the
delivery system or method of administration and is chosen in
accordance with conventional methods known in the art.
[0025] Most estrogens and progestins are orally active and that
route of administration (preferably in tablet or capsule form) is
therefore preferred. Pharmaceutical dosage forms for oral use can
be obtained through combination of the compounds of the present
invention with a solid excipient, optionally grinding a resulting
mixture, and processing the mixture of granules, after adding
suitable additional compounds, if desired, to obtain tablets or
cores. Tablet forms can include one or more of lactose, sucrose,
mannitol, sorbitol, calcium phosphates, corn starch, potato starch,
microcrystalline cellulose, gelatin, colloidal silicon dioxide,
talc, magnesium stearate, stearic acid, and other excipients,
colorants, fillers, binders, diluents, buffering agents, moistening
agents, preservatives, flavoring agents, dyes, disintegrating
agents, and pharmaceutically compatible carriers. Methods for
transdermal administration, including the associated manufacturing
methods, are well known in the art. In this connection, reference
may be had to U.S. Pat. Nos. 4,752,478, 4,685,911, 4,438,139 and
4,291,014, each incorporated herein by reference in their entirety
and for all purposes.
[0026] Dosage forms according to the invention can be placed in an
appropriate package and labeled for treatment. Such packages
(whether in the form of blister packs, tablet dispensers, or the
like) are referred to herein as kits, typically include the daily
dosages arranged for proper sequential administration. Preferred
kits contain multiple dosage forms in a synchronized, fixed
sequence, wherein the sequence or arrangement thereof corresponds
to the stages of daily administration. For example, dosage forms
can be provided in kit form containing about 18 to about 28 tablets
for a 28-day regimen, preferably about 21 to about 28 tablets.
These tablets are intended for ingestion on successive days. For
example, dosage forms can be provided in kit form containing about
28 to about 59 tablets for three or more 28-day regimens,
preferably about 51 to about 59 tablets. These tablets are intended
for ingestion on successive days. For a more long-term regimen, the
dosage forms can be provided in kit form containing at least about
60 tablets, and preferably at least about 81 to 89 tablets, and up
to 110 tablets, intended for ingestion on successive days.
Preferably administration is daily for at least 100 days. Daily
administration for at least 168 days, for at least 336 days, or for
a year or longer can also be effected. For administration of
multiple dosage forms from a kit, the provided labeling will
typically include, for example, instructions concerning the amount,
frequency and method of administration of each dosage form.
Preferred kits are those that include at least 100 dosage forms
that individually include at least one progestin and at least one
estrogen. Such kits can, in certain embodiments, include at least
about 185 of the dosage forms, at least about 275 of the dosage
forms, and/or at least about 365 of the dosage forms.
[0027] Although we do not wish to be bound by any particular theory
or mechanism of action, it is believed that the treatment regimens
of the present embodiment of the invention suppress the
hypothalamic-pituitary-ovarian axis but do not cause
hypoestrogenemia because of the exogenous estrogen component of the
embodiment of the invention replaces the suppressed endogenous
estrogen. It is believed that the combination of estrogen and
progestin at a constant dosage suppresses endogenous hormonal
fluctuations, as well as ovarian activity and the cyclic variations
in the production of estrogen, progesterone, luteinizing hormone,
and follicle-stimulating hormone.
[0028] The methods of the invention can be evaluated for their
effect on cycle-related symptoms using, for example, psychometric
scales that include a prospective daily symptoms chart or diary,
such as the 17-item Penn Daily Symptom Report (DSR) to evaluate
physical and psychological symptoms. Total score of the physical
and psychological symptoms is computed. The 17-item Penn DSR was
used to measure cycle-related symptoms in CRSS subjects who met
predefined criteria for a subgroup with dysmenorrhea, a subgroup
with moderate to severe cycle-related symptoms, and a subgroup with
mild to moderate cycle-related symptoms.
EXAMPLES
Example 1
[0029] Cycle-Related Symptoms Study Methods
[0030] The cycle-related symptom study (CRSS) was a 3-month study
that evaluated the effects of a continuous use regimen of progestin
and estrogen on cycle-related symptoms. Cycle-related symptoms were
evaluated among subgroups of female subjects with symptoms of: 1)
dysmenorrhea or; 2) two groups of cycle-related symptoms which
include the moderate to severe cycle-related symptoms subgroup, and
the mild to moderate cycle-related symptoms subgroup. Subjects were
to have a history of dysmenorrhea or symptoms of moderate to severe
cycle-related symptoms and must have met the study definition of
cycle-related symptoms during the screening menstrual cycle, with
data collected prospectively on a validated cycle-related symptoms
questionnaire, i.e., 17-item Penn Daily Symptom Report (DSR), which
included a 5-point Likert scale used by subjects to rate the
severity of symptoms. Each symptom was rated on a 5-point Likert
scale as follows: 0=none; 1=minimal; 2=moderate (not affecting
daily activities); 3=a lot (continuous, or interfering with
activities); and 4=severe (overwhelming and/or preventing daily
activities. The 17-item Penn DSR measured cycle-related symptoms
associated with a woman's menstrual cycle, which include, but are
not limited to, psychological symptoms (for example, mood change,
irritability, anxiety, lack of concentration, or decrease in sexual
desire) and physical symptoms (for example, dysmenorrhea, breast
tenderness, bloating, fatigue, or food cravings).
[0031] Subjects in the CRSS who met the criteria were expected to
complete the 17-item Penn DSR daily during the baseline cycle and
during pill packs 1, 2, and 3 (28 daily doses per pill pack).
[0032] The Endicott Work Productivity Scale (EWPS) was a
questionnaire administered to all subjects who qualified for the
two cycle-related symptoms subgroups or dysmenorrhea subgroup of
the CRSS and who received pay for work or did volunteer work. The
subjects were to complete the EWPS on days 7, 14, 21, and 28 of the
baseline screening cycle, and during pill packs 1, 2, and 3 (28
daily doses per pill pack).
[0033] The CRSS results showed that continuous-use regimen of
progestin and estrogen to female subjects reduced cycle-related
symptoms. The dosage of progestin (levonorgestrel, LNG: 90 .mu.g)
and estrogen (ethinyl estradiol, EE: 20 .mu.g) in a continuous-use
regimen to female subjects was effective in rapidly reducing
cycle-related symptoms associated with menses. Treatment of women
in the dysmenorrhea subgroup (n=259) showed that the LNG 90
.mu.g/EE 20 .mu.g continuous-use regimen was highly effective in
reducing cramps during the second and third month of treatment (no
significant effect was expected in the first month) and continuing
throughout the treatment period. Treatment of women in the moderate
to severe cycle-related symptoms subgroup (n=78) showed a reduction
by more than 50% in a broad range of cycle-related symptoms,
including moderate to severe cycle-related symptoms, starting
during the first month of treatment and continuing throughout the
treatment period. Treatment of women in the mild to moderate
cycle-related symptoms subgroup (n=36) showed that the LNG 90
.mu.g/EE 20 .mu.g continuous-use regimen was effective in reducing
most cycle-related symptoms in women with less severe cycle-related
symptoms.
[0034] Dysmenorrhea Subgroup
[0035] A total of 259 subjects met the protocol-defined criteria
for dysmenorrhea and were included in this subgroup analysis. Of
these subjects, 233 had complete data for pill pack 1, a total of
224 had complete data for pill pack 2, and 199 had complete data
for pill pack 3 (28 daily doses per pill pack).
[0036] The mean scores for cramps during pill pack 2 and pill pack
3 were decreased from baseline, indicating that the LNG 90 .mu.g/EE
20 .mu.g continuous-use regimen was highly effective in reducing
cramps in this subgroup. Because subjects began pill pack 1 on the
first day of menses, no significant effect of treatment on
dysmenorrhea was expected during pill pack 1.
[0037] Based on the mean maximum cramps score reported during the
first five days of the baseline cycle for each pill pack, the
severity of dysmenorrhea, as reflected in the mean maximum cramps
score, decreased with each pill pack. The decrease from baseline
was greatest during pill pack 2 and pill pack 3. Because subjects
began pill pack 1 on the first day of menses, no significant effect
of treatment on the severity of dysmenorrhea was expected during
pill pack 1.
[0038] Moderate to Severe Cycle-Related Symptoms Subgroup
[0039] A total of 78 subjects met the protocol-defined criteria for
moderate to severe cycle-related symptoms symptoms. The moderate to
severe cycle-related symptoms subgroup comprised subjects that had
one or more moderate to severe cycle-related symptoms. Of those
subjects, 70 had complete data for pill pack 1, a total of 64 had
complete data for pill pack 2, and 56 had complete data for pill
pack 3. Scores for moderate to severe cycle-related symptoms were
reported for six premenstrual days (i.e., days 23 to 28) and six
postmenstrual days (i.e., days 6 to 11), and were summarized as the
mean score for symptoms separately and then collectively as the
mean total score.
[0040] The mean total scores reported for premenstrual symptoms
(days 23 to 28) during pill pack 1, pill pack 2, and pill pack 3
were decreased from baseline. The mean score for each of 17
individual premenstrual symptoms also decreased from baseline.
Moderate to severe cycle-related symptoms was defined by the
protocol as a premenstrual total score .gtoreq.80 and a post
menstrual total score .ltoreq.50 on the 17-item Penn DSR at
baseline
[0041] While mean total score for postmenstrual symptoms was
slightly increased during pill pack 1, the mean premenstrual total
score was essentially equivalent to the mean postmenstrual score in
pill packs 2 and 3 (FIG. 1). In addition, the subscale scores for
the moderate to severe cycle-related symptoms subgroup with
symptoms related to mood, behavior, pain, or other physical
symptoms decreased during pill pack 1, and further decreased during
pill packs 2 and 3 (FIG. 2).
[0042] Mild to Moderate Cycle-Related Symptoms Subgroup
[0043] Subjects included in the mild to moderate cycle-related
symptoms subgroup had symptoms less severe than those required for
subjects in the moderate to severe cycle-related symptoms subgroup
yet still had cycle-related symptoms as defined by the protocol
(i.e., premenstrual score of .gtoreq.50 but .ltoreq.79 and
postmenstrual score <50 on the 17-item Penn DSR). Thirty-six
(36) subjects met the protocol-defined criteria. Of these subjects,
31 had complete data for pill pack 1, a total of 29 had complete
data for pill pack 2, and 26 had complete data for pill pack 3.
[0044] Mean total and mean individual scores for cycle-related
symptoms were reported for six premenstrual days (i.e., days 23 to
28) and six postmenstrual days (i.e., days 6 to 11). The mean total
scores reported for premenstrual (days 23 to 28) symptoms during
pill pack 1, pill pack 2, and pill pack 3 were decreased from
baseline.
[0045] For individual items, the premenstrual scores were reduced
from baseline during all three pill packs for the symptoms defined
as fatigue, aches, irritability, mood swings, swelling, craving
food, breast tenderness, and cramps. Individual items were
significantly reduced from baseline during pill pack 1 only for
symptoms defined as poor coordination, out of control, and nervous
tension. Anxiety and insomnia were reduced from baseline during
pill pack 1 and 2, but not pill pack 3. The symptoms defined as
headache and confusion were not significantly reduced in pill pack
1, but were in pill pack 2 and/or 3. Depression and crying were not
significantly reduced from baseline for any pill pack. The mean
total postmenstrual score increased from baseline to pill pack 1
and had no further increase in pill packs 2 and 3. A significant
increase in postmenstrual scores for some individual symptoms was
observed in each of the pill packs.
[0046] Endicott Work Productivity Scale
[0047] The Endicott Work Productivity Scale (EWPS) total scores
were evaluated for subjects in the dysmenorrhea subgroup both at
baseline and at evaluation week 1 of each pill pack. The mean total
EWPS score at baseline decreased by pill pack 1. Similar decreases
were observed from baseline to week 1 of each subsequent pill
pack.
[0048] The EWPS total scores were evaluated for subjects in the
moderate to severe cycle-related symptoms subgroup both at baseline
and at evaluation week 4 of each pill pack (FIG. 3). For this
subgroup, the mean total score at evaluation week 4 decreased from
baseline to pill pack 1 and decreased further in pill packs 2 and
3. The mean total EWPS scores at evaluation week 4 of each pill
pack were all decreased from baseline.
[0049] For the dysmenorrhea subgroup, the moderate to severe
cycle-related symptoms subgroup, and the mild to moderate
cycle-related symptoms subgroup, the EWPS scores were decreased
from baseline over the appropriate evaluation week after pill pack
1 and were 53% and 37% of the baseline score, respectively, by pill
pack 3, indicating improved work productivity. These results
represented rapid improvements in work productivity that was
evident as early as pill pack 1 and that continued to improve
through pill pack 3.
[0050] The LNG 90 .mu.g/EE 20 .mu.g continuous-use regimen was
effective in rapidly reducing cycle-related symptoms typically
associated with menses. Results from the dysmenorrhea subgroup
(n=259) showed that the LNG 90 .mu.g/EE 20 .mu.g continuous-use
regimen was highly effective in reducing cramps by pill pack 2
(second 28-day pack), a benefit that continued through pill pack 3
(third 28-day pack). Results from the moderate to severe
cycle-related symptoms subgroup (n=78) showed a reduction by more
than 50% in a broad range of moderate to severe cycle-related
symptoms by the end of pill pack 1 (first 28-day pack), and a
reduction of 80% during pill pack 3 (third 28-day pack). Results
from the mild to moderate cycle-related symptoms subgroup (n=36)
showed that the LNG 90 .mu.g/EE 20 .mu.g continuous-use regimen was
effective in reducing most cycle-related symptoms.
[0051] The reductions in cycle-related symptoms observed with the
LNG 90 .mu.g/EE 20 .mu.g continuous-use regimen were consistent
with improved work productivity among CRSS subjects who worked
and/or volunteered (dysmenorrhea subgroup and moderate to severe
cycle-related symptoms subgroup only). Among the subjects
evaluated, the EWPS scores were significantly decreased from
baseline after the first pill pack (first 28-day pack). These
results represented a rapid improvement in work productivity that
continued to improve through pill pack 3 (third 28-day pack).
* * * * *